[unreadable] [unreadable] Androgens are potent prostatic growth factors, and androgen-depletion is the sole strategy for the treatment and/or chemoprevention of prostate cancer. However, current androgen-depletion strategies for prostate cancer are only 75% effective at reducing dihydrotestosterone (DHT) levels and for prostate cancer chemoprevention are associated with significant side effects and risk. Consequently, we will test whether enhanced androgen catabolism can be an entirely new and complementary strategy for both the chemoprevention and/or treatment of prostate cancer, a strategy based on the following knowledge. (1) In the prostate, the androgen DHT, which activates the androgen receptor, is intracellularly synthesized from serum testosterone and catabolized primarily by AKR1C2 a 31-hydroxysteroid dehydrogenase and AKR1C1 a 32- hydroxysteroid dehydrogenase. (2) We reported that AKR1C2 (and the less active AKR1C1) gene expression in human prostate tumor samples is reduced and is associated with increased DHT content. (3) Increased AKR1C2 enzyme expression in prostate cancer cell lines due to transient or stable transfection can diminish DHT-dependent gene expression and subsequent cellular proliferation. (4) Inducers can also increase AKR1C2 and AKR1C1 enzyme expression in prostate cancer cell lines. Thus, the following Specific aims will test whether enhancing DHT catabolism, predominately by AKR1C2, can diminish DHT-dependent gene expression and tumor growth. In Specific Aim 1, we will determine whether enzyme AKR1C2 (and/or AKR1C1) can regulate intracellular DHT level and subsequently diminish DHT-dependent gene expression and growth of prostrate cancer cell line in culture or in athymic nude mice. In Specific Aim 2, we will test whether inducers of AKR1C2 (and AKR1C1) can enhance 3H-DHT catabolism, and diminish DHT-dependent gene expression and growth of prostate cancer cell lines in culture or in athymic mice. We will confirm that induction of AKR1C2 is required for diminution of DHT-dependent effects by these inducers. In Specific Aim 3, the effectiveness of enhanced DHT-catabolism by inducers will be evaluated in cell lines derived from spontaneous prostate tumors in a prostate specific conditional phosphatase and tensin homolog (Pten) homozygous deleted mouse strain (cPten-/-). The effectiveness of the inducer to delay the growth of spontaneous prostate tumors will also be evaluated in this mouse strain. Thus, this aim will test as a proof of principle the potential of enhancing DHT catabolism in an animal model. In summary, these three Specific Aims will establish the effectiveness of enhancing DHT catabolism to diminish DHT-dependent growth in model systems. If successful, these results will lead to future proposals to further develop this new strategy for achieving androgen-depletion for both the chemoprevention and/or to complement treatment of prostate cancer.Eliminating androgens in the prostate is the strategy used for the treatment and/or prevention of prostate cancer. New approaches are needed to treat prostate cancer because current treatments incompletely eliminate androgens. We will test whether enhancing androgen break down can delay the growth of prostate cancer cells and of spontaneous prostate tumors in a mouse strain, and thus prove that this new approach can be used for prostate cancer treatment and/or prevention. [unreadable] [unreadable] [unreadable]